Tunable compact nanosensor based on Fano resonance in a plasmonic waveguide system.
An ultracompact plasmonic refractive index sensor based on Fano resonance is proposed. The sensor comprises a metal-insulator-metal waveguide with a stub and a side-coupled split-ring resonator. The effect of structural parameters on Fano resonance and the refractive index sensitivity of the system are analyzed in detail by investigating the transmission spectrum. Simulation results show that Fano resonance has different dependences on the parameters of the sensor structure. The reason is further discussed based on the field pattern. The peak wavelength and lineshape can be easily tuned by changing the key parameters. Furthermore, dual Fano resonance effects with different frequency intervals are obtained, which are mainly induced by the symmetry breaking of the structure. The proposed sensor yields sensitivity higher than 1.4×103 nm/RIU and a figure of merit of 1.2×105. The sensitivity and figure of merit can be further improved by optimizing the geometry parameters.


Promotion of tumor progression by exosome transmission of circular RNA circSKA3.
We performed in vitro and in vivo experiments to investigate the role of the circular RNA circSKA3 in tumor development. We examined the effects of circSKA3 on mediating breast cancer metastasis. In vitro, we found that the circular RNA circSKA3 was transferred between breast cancer cells, which were decreased by inhibiting exosome secretion. In vivo, circSKA3-containing exosomes potentiated tumor development and invasion that were inhibited by blocking exosome transmission. The ascites isolated from tumor-bearing mice or breast cancer patients showed high levels of circSKA3 and integrin β1. Single-cell culture and single-cell PCR showed that circSKA3 was heterogeneously expressed, the cells expressing higher levels of circSKA3 had a higher potential to form large colonies. This property was similar to c-myc, but circSKA3 expression had no correlation with c-myc levels. The effects of circSKA3 on cell migration and invasion appeared to predominate c-myc functions. By releasing circSKA3-containing exosomes to cancer cells expressing lower levels of circSKA3, the large colonies could regulate the activities of small colonies, enhancing the tumor-forming capacity of the entire population. Thus, we provide evidence that the transmission of circular RNAs in tumor-derived exosomes may allow for the maintenance of advantageous invasive sub-clones in breast cancer.


Quantifying the reduction in potential health risks by determining the sensitivity of poliovirus type 1 chat strain and rotavirus SA-11 to electron beam irradiation of iceberg lettuce and spinach.
Fresh produce, such as lettuce and spinach, serves as a route of food-borne illnesses. The U.S. FDA has approved the use of ionizing irradiation up to 4 kGy as a pathogen kill step for fresh-cut lettuce and spinach. The focus of this study was to determine the inactivation of poliovirus and rotavirus on lettuce and spinach when exposed to various doses of high-energy electron beam (E-beam) irradiation and to calculate the theoretical reduction in infection risks that can be achieved under different contamination scenarios and E-beam dose applications. The D(10) value (dose required to reduce virus titers by 90%) (standard error) of rotavirus on spinach and lettuce was 1.29 (± 0.64) kGy and 1.03 (± 0.05) kGy, respectively. The D(10) value (standard error) of poliovirus on spinach and lettuce was 2.35 (± 0.20) kGy and 2.32 (± 0.08) kGy, respectively. Risk assessment of data showed that if a serving (∼14 g) of lettuce was contaminated with 10 PFU/g of poliovirus, E-beam irradiation at 3 kGy will reduce the risk of infection from >2 in 10 persons to approximately 6 in 100 persons. Similarly, if a serving size (∼0.8 g) of spinach is contaminated with 10 PFU/g of rotavirus, E-beam irradiation at 3 kGy will reduce infection risks from >3 in 10 persons to approximately 5 in 100 persons. The results highlight the value of employing E-beam irradiation to reduce public health risks but also the critical importance of adhering to good agricultural practices that limit enteric virus contamination at the farm and in packing houses.


Structural Insights into APOBEC3-Mediated Lentiviral Restriction.
Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins-A3G, A3F, A3H, and A3D-restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.


The effect of helmets on the risk of head and neck injuries among skiers and snowboarders: a meta-analysis.
The prevention of head injuries in alpine activities has focused on helmets. However, no systematic review has examined the effect of helmets on head and neck injuries among skiers and snowboarders. We searched electronic databases, conference proceedings and reference lists using a combination of the key words "head injury or head trauma," "helmet" and "skiing or snowboarding." We included studies that used a control group; compared skiers or snowboarders with and without helmets; and measured at least one objectively quantified outcome (e.g., head injury, and neck or cervical injury). We included 10 case-control, 1 case-control/case-crossover and 1 cohort study in our analysis. The pooled odds ratio (OR) indicated that skiers and snowboarders with a helmet were significantly less likely than those without a helmet to have a head injury (OR 0.65, 95% confidence interval [CI] 0.55-0.79). The result was similar for studies that used controls without an injury (OR 0.61, 95% CI 0.36-0.92), those that used controls with an injury other than a head or neck injury (OR 0.63, 95% CI 0.52-0.80) and studies that included children under the age of 13 years (OR 0.41, 95% CI 0.27-0.59). Helmets were not associated with an increased risk of neck injury (OR 0.89, 95% CI 0.72-1.09). Our findings show that helmets reduce the risk of head injury among skiers and snowboarders with no evidence of an increased risk of neck injury.


Relativity and the lead-acid battery.
The energies of the solid reactants in the lead-acid battery are calculated ab initio using two different basis sets at nonrelativistic, scalar-relativistic, and fully relativistic levels, and using several exchange-correlation potentials. The average calculated standard voltage is 2.13 V, compared with the experimental value of 2.11 V. All calculations agree in that 1.7-1.8 V of this standard voltage arise from relativistic effects, mainly from PbO2 but also from PbSO4.


Oxford's clinical experience in the development of high intensity focused ultrasound therapy.
High Intensity Focused Ultrasound (HIFU) capably bridges the disciplines of surgery, oncology and biomedical engineering science. It provides the precision associated with a surgical tool whilst remaining a truly non-invasive technique. Oxford has been a centre for both clinical and preclinical research in HIFU over the last twenty years. Research into this technology in the UK has a longer history, with much of the early research being carried out by Professor Gail ter Haar and her team at the Institute of Cancer Research at Sutton in Surrey. A broad range of potential applications have been explored extending from tissue ablation to novel drug delivery. This review presents Oxford's clinical studies and applications for the development of this non-invasive therapy. This includes treatment of solid abdominal tumours comprising those of the liver, kidney, uterus, pancreas, pelvis and prostate. It also briefly introduces preclinical and translational works that are currently being undertaken at the Institute of Biomedical Engineering, University of Oxford. The safety, wide tolerability and effectiveness of this technology is comprehensively demonstrated across these studies. These results can facilitate the incorporation of HIFU as a key clinical management strategy.


Impact of Antimony(V) on Iron(II)-Catalyzed Ferrihydrite Transformation Pathways: A Novel Mineral Switch for Feroxyhyte Formation.
The environmental mobility of antimony (Sb) is controlled by interactions with iron (Fe) oxides, such as ferrihydrite. Under near-neutral pH conditions, Fe(II) catalyzes the transformation of ferrihydrite to more stable phases, thereby potentially altering the partitioning and speciation of associated Sb. Although largely unexplored, Sb itself may also influence ferrihydrite transformation pathways. Here, we investigated the impact of Sb on the Fe(II)-induced transformation of ferrihydrite at pH 7 across a range of Sb(V) loadings (Sb:Fe(III) molar ratios of 0, 0.003, 0.016, and 0.08). At low and medium Sb loadings, Fe(II) induced rapid transformation of ferrihydrite to goethite, with some lepidocrocite forming as an intermediate phase. In contrast, the highest Sb:Fe(III) ratio inhibited lepidocrocite formation, decreased the extent of goethite formation, and instead resulted in substantial formation of feroxyhyte, a rarely reported FeOOH polymorph. At all Sb loadings, the transformation of ferrihydrite was paralleled by a decrease in aqueous and phosphate-extractable Sb concentrations. Extended X-ray absorption fine structure spectroscopy showed that this Sb immobilization was attributable to incorporation of Sb into Fe(III) octahedral sites of the neo-formed minerals. Our results suggest that Fe oxide transformation pathways in Sb-contaminated systems may strongly differ from the well-known pathways under Sb-free conditions.


Proteomic profiling of a robust Wolbachia infection in an Aedes albopictus mosquito cell line.
Wolbachia pipientis, a widespread vertically transmitted intracellular bacterium, provides a tool for insect control through manipulation of host-microbe interactions. We report proteomic characterization of wStr, a Wolbachia strain associated with a strong cytoplasmic incompatibility phenotype in its native host, Laodelphax striatellus. In the Aedes albopictus C/wStr1 mosquito cell line, wStr maintains a robust, persistent infection. MS/MS analyses of gel bands revealed a protein 'footprint' dominated by Wolbachia-encoded chaperones, stress response and cell membrane proteins, including the surface antigen WspA, a peptidoglycan-associated lipoprotein and a 73 kDa outer membrane protein. Functional classifications and estimated abundance levels of 790 identified proteins suggested that expression, stabilization and secretion of proteins predominate over bacterial genome replication and cell division. High relative abundances of cysteine desulphurase, serine/glycine hydroxymethyl transferase, and components of the α-ketoglutarate dehydrogenase complex in conjunction with above average abundances of glutamate dehydrogenase and proline utilization protein A support Wolbachia genome-based predictions for amino acid metabolism as a primary energy source. wStr expresses 15 Vir proteins of a Type IV secretion system and its transcriptional regulator. Proteomic characterization of a robust insect-associated Wolbachia strain provides baseline information that will inform further development of in vitro protocols for Wolbachia manipulation.


Short therapy with amoxicillin-clavulanate and corticosteroids in acute sinusitis: results of a multicentre study in adults.
Evolution of bacterial resistance shortens antibiotic treatment in ENT infections. The efficacy and tolerance of amoxicillin-clavulanate (ACA), with and without associated short steroid therapy, was evaluated in acute sinusitis of adults at a dosage of 1.5 g/d for 5 d vs. 10 d. This multicentre, randomized, double-blind, placebo-controlled study included 433 patients, 417 of whom were suitable for intent-to-treat (ITT) analysis. The therapeutic success rate in the ITT population, assessed according to strict clinical and radiological criteria, was respectively, 80% and 85% in the 5-d and 10-d treatment groups. Due to the statistical risks that were evidenced, the 2 durations of treatment could not be considered equivalent. The analysis of medical history shows that some risk factors (recurrence of sinusitis, previous surgical sinus drainage) seem to promote therapeutic failure and that 5-d treatment is inappropriate in these patients. The persistence of therapeutic success on day 30 was not influenced by the initial duration of treatment. The efficacy and good tolerance of ACA in acute sinusitis in adults were confirmed. Further studies will be needed to define the indications of short treatments better, which seem to be indicated in the absence of specific risk factors.


Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents.
Resolution of inflammation and induction of immune tolerance are essential to stabilize immune homeostasis and to limit the occurrence of exacerbated inflammatory and autoimmune conditions. Multiple mechanisms act together to ensure the re-establishment of immune homeostasis and maintenance of tolerance. The identification of endogenous factors that regulate these processes is crucial for the development of new therapies for inflammatory/autoimmune conditions. Neuropeptides produced during an ongoing inflammatory response emerged as endogenous anti-inflammatory agents that participate in processes leading to the resolution of inflammation and maintenance of tolerance. Anti-inflammatory neuropeptides and hormones such as vasoactive intestinal peptide, urocortin, adrenomedullin, melanocyte stimulating hormone, ghrelin, and cortistatin have beneficial effects in a variety of experimental inflammatory and autoimmune models. Their therapeutic effect has been attributed to their capacity to downregulate innate immunity, to inhibit antigen-specific T(H)1-driven responses, and to generate regulatory T cells. Finally, some of these neuropeptides have been identified as mediators of innate defense acting as natural antimicrobial peptides. Here we present the research findings in the neuropeptide immunoregulatory field, and examine possible therapies based on anti-inflammatory neuropeptides and hormones as a new pharmacologic platform.


Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs.
We investigated the regional distribution and cellular localization of mRNA coding for the cAMP-specific phosphodiesterase 7A (PDE7A) in rat brain and several peripheral organs by in situ hybridization histochemistry. The regional expression of two splice variants, PDE7A1 and PDE7A2, was examined by RT-PCR using RNA extracted from several brain regions. PDE7A mRNA was found to be widely distributed in rat brain in both neuronal and nonneuronal cell populations. The highest levels of hybridization were observed in the olfactory bulb, olfactory tubercle, hippocampus, cerebellum, medial habenula nucleus, pineal gland, area postrema, and choroid plexus. Positive hybridization signals were also detected in other areas, such as raphe nuclei, temporal and entorhinal cortex, pontine nuclei, and some cranial nerve motor nuclei. Both mRNA splice forms were differentially distributed in several areas of the brain with the striatum expressing only PDE7A1 and the olfactory bulb and spinal cord expressing PDE7A2 exclusively. In peripheral organs the highest levels of PDE7A hybridization were seen in kidney medulla, although testis, liver, adrenal glands, thymus, and spleen also presented high hybridization signal. These results are consistent with PDE7A being involved in the regulation of cAMP signaling in many brain functions. The consistent colocalization with PDE4 mRNAs suggests that PDE7A could have an effect on memory, depression, and emesis. The results offer clear anatomical and functional systems in which to investigate future specific PDE7 inhibitors.


Diffusion tensor imaging in preterm infants with punctate white matter lesions.
Our aim was to compare white matter (WM) microstructure in preterm infants with and without punctate WM lesions on MRI using tract-based spatial statistics (TBSS) and probabilistic tractography. We studied 23 preterm infants with punctate lesions, median GA at birth 30 (25-35) wk, and 23 GA- and sex-matched preterm controls. TBSS and tractography were performed to assess differences in fractional anisotropy (FA) between the two groups at term equivalent age. The impact of lesion load was assessed by performing linear regression analysis of the number of lesions on term MRI versus FA in the corticospinal tracts in the punctate lesions group. FA values were significantly lower in the posterior limb of the internal capsule, cerebral peduncles, decussation of the superior cerebellar peduncles, superior cerebellar peduncles, and pontine crossing tract in the punctate lesions group. There was a significant negative correlation between lesion load at term and FA in the corticospinal tracts (p = 0.03, adjusted r² = 0.467). In conclusion, punctate lesions are associated with altered microstructure in the WM fibers of the corticospinal tract at term equivalent age.


Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release.
In cardiac ventricular myocytes, events crucial to excitation-contraction coupling take place in spatially restricted microdomains known as dyads. The movement and dynamics of calcium (Ca2+) ions in the dyad have often been described by assigning continuously valued Ca2+ concentrations to one or more dyadic compartments. However, even at its peak, the estimated number of free Ca2+ ions present in a single dyad is small (approximately 10-100 ions). This in turn suggests that modeling dyadic calcium dynamics using laws of mass action may be inappropriate. In this study, we develop a model of stochastic molecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyR2s) that describes: a), known features of dyad geometry, including the space-filling properties of key dyadic proteins; and b), movement of individual Ca2+ ions within the dyad, as driven by electrodiffusion. The model enables investigation of how local Ca2+ signaling is influenced by dyad structure, including the configuration of key proteins within the dyad, the location of Ca2+ binding sites, and membrane surface charges. Using this model, we demonstrate that LCC-RyR2 signaling is influenced by both the stochastic dynamics of Ca2+ ions in the dyad as well as the shape and relative positioning of dyad proteins. Results suggest the hypothesis that the relative placement and shape of the RyR2 proteins helps to "funnel" Ca2+ ions to RyR2 binding sites, thus increasing excitation-contraction coupling gain.


Generation of 63 fs 4.1 MW peak power pulses from a parabolic fiber amplifier operated beyond the gain bandwidth limit.
We report the generation of 63 fs pulses of 290 nJ energy and 4.1 MW peak power at 1050 nm based on the use of a polarization-maintaining ytterbium-doped fiber parabolic amplification system. We demonstrate that operation of the amplifier beyond the gain bandwidth limit plays a key role on the sufficient recompressibility of the pulses in a standard grating pair compressor. This results from the accumulated asymmetric nonlinear spectral phase and the good overall third-order dispersion compensation in the system.


Adenovirus-delivered PDCD5 counteracts adriamycin resistance of osteosarcoma cells through enhancing apoptosis and inhibiting Pgp.
In the present study, we investigated the roles of PDCD5 (programmed cell death 5) in multidrug re-sistance (MDR) of osteosarcoma cells and the possible lurking mechanisms. An adenovirus expression vector of PDCD5 was constructed and transfected into human adriamycin-resistant osteosarcoma cell line Saos-2/ADM. We found that up-regulation of PDCD5 could significantly enhance the sensitivity of Saos-2/ADM cells towards vincristine, methotrexate, cisplatin and arsenic trioxide (As2O3), and could decrease the capacity of cells to efflux adriamycin. PDCD5 could significantly down regulate the expression of P-glycoprotein (Pgp), but not affect the expression of multidrug resistance associated protein (MRP) or the glutathione S-transferase (GST). PDCD5 was also able to significantly increase the apoptotic activity of modified osteosarcoma cells. Further study of the biological functions of PDCD5 might be helpful in the understanding of the mechanisms of multidrug resistance (MDR) in osteosarcoma and exploring PDCD5 based adjuvant genetic therapy.


Care of the psychotic self-amputee undergoing replantation.
The acutely psychotic self-amputee may be brought to the emergency room out of control, refusing treatment. Although these conditions make it difficult for the surgeon to provide restorative surgery, these patients may be quite grateful when resolution of psychosis restores realistic thinking and better judgment. This article describes the treatment of two such patients and provides practical guidelines for general behavioral management. The focal point of the approach is the formation of a surgeon/psychiatrist team that actively and consistently confronts and manages the disturbed behavior from the time the patient arrives in the emergency room until after discharge. Responsibility for deciding to operate when the patient is verbally refusing must be shared by surgeon and psychiatrist. Both surgeon and psychiatrist must be active in the treatment, each contributing his particular expertise to the collaborative effort.


MAPK/ERK and PI3K/AKT signaling pathways are activated in adolescent and adult acute lymphoblastic leukemia.
The mitogen-activated protein kinase (MAPK)/ERK signaling cascade and the phosphoinosytol-3 phosphate/Akt (PI3K/Akt) pathways are involved in proliferation and differentiation of hematopoietic cells. The frequency of PI3K/Akt and MAPK pathway activation in adult acute lymphoblastic leukemia (ALL) still need to be elucidated. To assess the activity and prognostic implications of MAPK/ERK and PI3K/Akt pathways in adult (ALL). We examined 28 precursor-B-cell ALL and 6 T-cell primary ALL samples. Flow cytometry was employed to analyze the expression levels of phosphorylated ERK and phosphorylated Akt. Ten out of 15 (67%) ALL fresh samples (7 B-cell, 3 T-cell) showed constitutive p-ERK expression. The p-ERK mean fluorescent index ratio (MFI (R)) showed a tendency to be higher in ALL than in normal T lymphocytes (1.26 [0.74-3.10] vs. 1.08 [1.02-1.21], respectively [p = .069]) and was significantly lower than in leukemic cell lines (median MFI (R) 3.83 [3.71-5.97] [p < .001]). Expression of p-Akt was found in 35% (12/34) (10 B-cell, 2 T-cell). The median MFI (R) expression for p-Akt in primary blast cell was 1.13 (0.48-9.90) compared to 1.01 (1.00-1.20) in normal T lymphocytes (p = ns) and lower than in leukemic cell lines (median MFI (R) 2.10 [1.77-3.40] [p = .037]). Moreover, expression of p-ERK was negatively associated with the expression of CD34 (1.22 [0.74-1.33] vs. 1.52 [1.15-3.10] for CD34(+) and CD34(-) group, respectively, p = .009). Our findings suggest that both MAPK/ERK and PI3K/Akt are constitutively activated in adult ALL, indicating a targeted therapy potential for ALL by using inhibitors of these pathways.


[Population-demographic and clinico-genetic characteristics of Huntington chorea in one region of Azerbaijan].
The data are presented on prevalence and clinical patterns of Huntington disease in Shamkhor region of Azerbaijan, where about 126.8 thousand inhabitants live. Population, demographic and genealogical data show that high prevalence of Huntington disease in that region is determined by the founder effects, reinforced later by extended reproduction of the population. Linkage analysis using the affected sib-pair method failed to reveal a linkage between Huntington's chorea locus and HLA, AB0, MN systems. Significant probability of linkage to Huntington's chorea locus was calculated for Gc marker.


MLH1 and XRCC1 polymorphisms in Mexican patients with colorectal cancer.
DNA repair proteins maintain DNA integrity; polymorphisms in genes coding for these proteins can increase susceptibility to colorectal cancer (CRC) development. We analyzed a possible association of MLH1 -93G>A and 655A>G and XRCC1 Arg194Trp and Arg399Gln polymorphisms with CRC in Mexican patients. Genomic DNA samples were obtained from peripheral blood of 108 individuals with CRC (study group) at diagnosis and 120 blood donors (control group) from Western Mexico; both groups were mestizos. The polymorphisms were detected by PCR-RFLP. Association was estimated by calculating the odds ratio (OR). We found that the MLH1 and XRCC1 polymorphisms were in Hardy- Weinberg equilibrium. The MLH1 655A>G polymorphism in the 655G allele was associated with a 2-fold increase risk for CRC (OR = 2.04 and 95% confidence interval (95%CI) = 1.12-3.69; P < 0.01), while the MLH1 -93G>A polymorphism allele was associated with a protective effect (OR = 0.60, 95%CI = 0.40-0.89; P = 0.01 in the -93A allele and OR = 0.32, 95%CI = 0.13-0.79; P = 0.01 in the AA genotype). The XRCC1 Arg194Trp and Arg399Gln polymorphisms did not show any significant associations. In conclusion, we found that MLH1 -93G>A and 655A>G polymorphisms are associated with CRC in Mexican patients.


Corticosteroid use during pregnancy and risk of orofacial clefts.
The association between the risk of orofacial clefts in infants and the use of corticosteroids during pregnancy is unclear from the available evidence. We conducted a nationwide cohort study of all live births in Denmark over a 12-year period. We collected data on all live births in Denmark from Jan. 1, 1996, to Sept. 30, 2008. We included live births for which information was available from nationwide health registries on the use of corticosteroids during pregnancy, the diagnosis of an orofacial cleft and possible confounders. There were 832,636 live births during the study period. Exposure to corticosteroids during the first trimester occurred in 51,973 of the pregnancies. A total of 1232 isolated orofacial clefts (i.e., cleft lip, cleft palate, or cleft lip and cleft palate) were diagnosed within the first year of life, including 84 instances in which the infant had been exposed to corticosteroids during the first trimester of pregnancy. We did not identify any statistically significant increased risk of orofacial clefts associated with the use of corticosteroids: cleft lip with or without cleft palate, prevalence odds ratio (OR) 1.05 (95% confidence interval [CI] 0.80-1.38]; cleft palate alone, prevalence OR 1.23 (95% CI 0.83-1.82). Odds ratios for risk of orofacial clefts by method of delivery (i.e., oral, inhalant, nasal spray, or dermatologic and other topicals) were consistent with the overall results of the study and did not display significant heterogeneity, although the OR for cleft lip with or without cleft palate associated with the use of dermatologic corticosteroids was 1.45 (95% CI 1.03-2.05). Our results add to the safety information on a class of drugs commonly used during pregnancy. Our study did not show an increased risk of orofacial clefts with the use of corticosteroids during pregnancy. Indepth investigation of the pattern of association between orofacial clefts and the use of dermatologic corticosteroids during pregnancy indicated that this result did not signify a causal connection and likely arose from multiple statistical comparisons.


Anatomy of the temporal bone.
High resolution computed tomography has proved to be invaluable in the evaluation of the temporal bone, and demonstrates its bony anatomy in exquisite detail. Furthermore, the role of magnetic resonance imaging, especially with improving high resolution techniques, has continued to expand in the past decade. A thorough understanding of normal temporal bone anatomy is a requisite for accurate radiologic evaluation. The ensuing discussion is an attempt to summarize the normal temporal bone anatomy with emphasis on clinically relevant structures, temporal bone pneumatization, and common anatomic variants.


Neutrophil-to-Lymphocyte Ratio Predicts Death in Acute-on-Chronic Liver Failure Patients Admitted to the Intensive Care Unit: A Retrospective Cohort Study.
The neutrophil-to-lymphocyte ratio (NLR) is an inflammation score recognized as associated with outcome. Although inflammation has been shown to correlate with the development of acute-on-chronic liver failure (ACLF), we sought to investigate the role of NLR in predicting 90-day mortality in cirrhotic patients experiencing ACLF. We performed a retrospective cohort study involving a total of 108 consecutive cirrhotic patients admitted in the intensive care unit (ICU). NLR, clinical and biological data were recorded. Of the total, 75 patients had ACLF. The 90-day mortality rate was 53%. ACLF patients displayed higher NLR values in comparison with cirrhotic patients without ACLF throughout the ICU stay. NLR proved more elevated in nonsurvivors ACLF patients, with mortality correlating with increasing quartiles of NLR. On multivariable Cox regression analysis, NLR was found to be a predictor of mortality along with the Sequential Organ Failure Assessment (SOFA) score and mechanical ventilation requirement. The model for end-stage liver disease (MELD) score was not predictive of 90-days mortality. Performance analysis revealed an area under curve of 0.71 [95% confidence interval: 0.59-0.82] regarding NLR capacity to predict 90-days mortality. When including NLR, SOFA score, and mechanical ventilation requirement into the final model, the area under curve was significantly higher (0.81 [95% confidence interval: 0.72-0.91]).These findings suggest that NLR is associated with mortality in ACLF patients admitted to the ICU. Combining NLR, SOFA score, and the need for mechanical ventilation could be a useful prognostic tool to identify ACLF patients at a higher risk of mortality.


Transcriptional landscape and clinical utility of enhancer RNAs for eRNA-targeted therapy in cancer.
Enhancer RNA (eRNA) is a type of noncoding RNA transcribed from the enhancer. Although critical roles of eRNA in gene transcription control have been increasingly realized, the systemic landscape and potential function of eRNAs in cancer remains largely unexplored. Here, we report the integration of multi-omics and pharmacogenomics data across large-scale patient samples and cancer cell lines. We observe a cancer-/lineage-specificity of eRNAs, which may be largely driven by tissue-specific TFs. eRNAs are involved in multiple cancer signaling pathways through putatively regulating their target genes, including clinically actionable genes and immune checkpoints. They may also affect drug response by within-pathway or cross-pathway means. We characterize the oncogenic potential and therapeutic liability of one eRNA, NET1e, supporting the clinical feasibility of eRNA-targeted therapy. We identify a panel of clinically relevant eRNAs and developed a user-friendly data portal. Our study reveals the transcriptional landscape and clinical utility of eRNAs in cancer.


Inhomogenous capillary flow and its prevention by verapamil and hydralazine in the cardiomyopathic Syrian hamster.
There is clinical evidence that human dilated cardiomyopathy is related to microcirculatory disorders. We used an experimental preparation of the disease that consisted of a study of the microcirculation of 45 cardiomyopathic Syrian and 18 control hamsters with timed plasma staining. To investigate dynamic vascular disorders a double injection technique was used that permitted demonstration of all permanently and temporarily perfused capillaries in the same animal. The results showed a total capillary density of 3423 +/- 470 capillaries/mm2 in the cardiomyopathic hamster during the premyocytolic phase (30 days of age) and that of 3289 +/- 506 capillaries/mm2 during the myocytolytic phase (44 days). These values were not significantly different from those in the control group (3349 +/- 473 capillaries/mm2 at 30 days and 3383 +/- 556 capillaries/mm2 at 44 days). However, tissue areas with extended coronary transit times were detected only in the cardiomyopathic hamsters. These areas were of the same individual and cumulative size at 30 days (diameter approximately 200 micron, 4% of the tissue) as the myocytolytic zones at 44 days. In cardiomyopathic hamsters verapamil and hydralazine prevented both hypoperfusion and myocytolysis. The results favor the view that microcirculatory disorders generate tissue damage in the cardiomyopathic hamster and that these disorders can be prevented through treatment with the calcium antagonist verapamil or with the vasodilator hydralazine.


Quantitative proteomics reveal up-regulated protein expression of the SET complex associated with hepatocellular carcinoma.
We combined culture-derived isotope tags (CDITs) with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) to extensively survey abnormal protein expression associated with hepatocellular carcinoma (HCC) in clinical tissues. This approach yielded an in-depth quantitated proteome of 1360 proteins. Importantly, 267 proteins were significantly regulated with a fold-change of at least 1.5. The proteins up-regulated in HCC tissues are involved in regulatory processes, such as the granzyme A-mediated apoptosis pathway (The GzmA pathway). The SET complex, a central component in the GzmA pathway, was significantly up-regulated in HCC tissue. The elevated expressions of all of the SET complex components were validated by Western blotting. Among them, ANP32A and APEX1 were further investigated by immunohistochemistry staining using tissue microarrays (59 cases), confirming their overexpression in tumors. The up-regulation and nuclear accumulations of APEX1 was associated not only with HCC malignancy but also with HCC differentiation in 96 clinical HCC cases. Our work provided a systematic and quantitative analysis and demonstrated key changes in clinical HCC tissues. These proteomic signatures could help to unveil the underlying mechanisms of hepatocarcinogenesis and may be useful for the discovery of candidate biomarkers.


Nested PCR-denaturing gradient gel electrophoresis approach to determine the diversity of sulfate-reducing bacteria in complex microbial communities.
Here, we describe a three-step nested-PCR-denaturing gradient gel electrophoresis (DGGE) strategy to detect sulfate-reducing bacteria (SRB) in complex microbial communities from industrial bioreactors. In the first step, the nearly complete 16S rRNA gene was amplified using bacterial primers. Subsequently, this product was used as a template in a second PCR with group-specific SRB primers. A third round of amplification was conducted to obtain fragments suitable for DGGE. The largest number of bands was observed in DGGE patterns of products obtained with primers specific for the Desulfovibrio-Desulfomicrobium group, indicating a large diversity of these SRBs. In addition, members of other phylogenetic SRB groups, i.e., Desulfotomaculum, Desulfobulbus, and Desulfococcus-Desulfonema-Desulfosarcina, were detected. Bands corresponding to Desulfobacterium and Desulfobacter were not detected in the bioreactor samples. Comparative sequence analysis of excised DGGE bands revealed the identity of the community members. The developed three-step PCR-DGGE strategy is a welcome tool for studying the diversity of sulfate-reducing bacteria.


The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.
To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.


Rare Complications of Cervical Spine Surgery: Horner's Syndrome.
A multicenter retrospective case series. Horner's syndrome is a known complication of anterior cervical spinal surgery, but it is rarely encountered in clinical practice. To better understand the incidence, risks, and neurologic outcomes associated with Horner's syndrome, a multicenter study was performed to review a large collective experience with this rare complication. We conducted a retrospective multicenter case series study involving 21 high-volume surgical centers from the AOSpine North America Clinical Research Network. Medical records for 17 625 patients who received subaxial cervical spine surgery from 2005 to 2011 were reviewed to identify occurrence of 21 predefined treatment complications. Descriptive statistics were provided for baseline patient characteristics. Paired t test was used to analyze changes in clinical outcomes at follow-up compared to preoperative status. In total, 8887 patients who underwent anterior cervical spine surgery at the participating institutions were screened. Postoperative Horner's syndrome was identified in 5 (0.06%) patients. All patients experienced the complication following anterior cervical discectomy and fusion. The sympathetic trunk appeared to be more vulnerable when operating on midcervical levels (C5, C6), and most patients experienced at least a partial recovery without further treatment. This collective experience suggests that Horner's syndrome is an exceedingly rare complication following anterior cervical spine surgery. Injury to the sympathetic trunk may be limited by maintaining a midline surgical trajectory when possible, and performing careful dissection and retraction of the longus colli muscle when lateral exposure is necessary, especially at caudal cervical levels.


Optimized design and assessment of whole genome tiling arrays.
Recent advances in microarray technologies have made it feasible to interrogate whole genomes with tiling arrays and this technique is rapidly becoming one of the most important high-throughput functional genomics assays. For large mammalian genomes, analyzing oligonucleotide tiling array data is complicated by the presence of non-unique sequences on the array, which increases the overall noise in the data and may lead to false positive results due to cross-hybridization. The ability to create custom microarrays using maskless array synthesis has led us to consider ways to optimize array design characteristics for improving data quality and analysis. We have identified a number of design parameters to be optimized including uniqueness of the probe sequences within the whole genome, melting temperature and self-hybridization potential. We introduce the uniqueness score, U, a novel quality measure for oligonucleotide probes and present a method to quickly compute it. We show that U is equivalent to the number of shortest unique substrings in the probe and describe an efficient greedy algorithm to design mammalian whole genome tiling arrays using probes that maximize U. Using the mouse genome, we demonstrate how several optimizations influence the tiling array design characteristics. With a sensible set of parameters, our designs cover 78% of the mouse genome including many regions previously considered 'untilable' due to the presence of repetitive sequence. Finally, we compare our whole genome tiling array designs with commercially available designs. Source code is available under an open source license from http://www.ebi.ac.uk/~graef/arraydesign/.


Chemiluminescence assay of N-acetyl-beta-D-glucosaminidase in urine using o-aminophthalylhydrazido-N-acetyl-beta-D-glucosaminide.
The chemiluminescence assay of urinary N-acetyl-beta-D-glucosaminidase using o-aminophthalylhydrazido-N-acetyl-beta-D-glucosaminide as the substrate was examined. Under optimized conditions, a linear chemiluminescence response to the standard N-acetyl-beta-D-glucosaminidase (NAGase) of different concentrations was observed with a correlation coefficient of 0.999 over the range of 0.3 to 20 I.U./l. The present method was compared with the prevalent method using p-nitrophenyl-N-acetyl-beta-D-glucosaminide in the assay of 20 urine samples from healthy subjects, and the correlation coefficient of 0.891 was obtained.


The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis.
Saliva is a key factor that contributes to the high efficiency of wound healing in the oral mucosa. This is not only attributed to physical cues but also to the presence of specific peptides in the saliva, such as histatins. Histatin-1 is a 38 aa antimicrobial peptide, highly enriched in human saliva, which has been previously reported to promote the migration of oral keratinocytes and fibroblasts in vitro However, the participation of histatin-1 in other crucial events required for wound healing, such as angiogenesis, is unknown. Here we demonstrate that histatin-1 promotes angiogenesis, as shown in vivo, using the chick chorioallantoic membrane model, and by an in vitro tube formation assay, using both human primary cultured endothelial cells (HUVECs) and the EA.hy926 cell line. Specifically, histatin-1 promoted endothelial cell adhesion and spreading onto fibronectin, as well as endothelial cell migration in the wound closure and Boyden chamber assays. These actions required the activation of the Ras and Rab interactor 2 (RIN2)/Rab5/Rac1 signaling axis, as histatin-1 increased the recruitment of RIN2, a Rab5-guanine nucleotide exchange factor (GEF) to early endosomes, leading to sequential Rab5/Rac1 activation. Accordingly, interfering with either Rab5 or Rac1 activities prevented histatin-1-dependent endothelial cell migration. Finally, by immunodepletion assays, we showed that salivary histatin-1 is required for the promigratory effects of saliva on endothelial cells. In conclusion, we report that salivary histatin-1 is a novel proangiogenic factor that may contribute to oral wound healing.-Torres, P., Díaz, J., Arce, M., Silva, P., Mendoza, P., Lois, P., Molina-Berríos, A., Owen, G. I., Palma, V., Torres, V. A. The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis.


[Bacteremia originated in intravascular cannulae: an epidemiologic study of 91 episodes].
This reports the analysis of an epidemiologic study of intravascular cannula bacteriemia (ICB) in a Barcelona university hospital. There were 91 episodes of ICB representing the 26.7% of the total hospital bacteriemia. In 60.6% of ICB the diagnosis was made in an intensive care area. The most common microorganisms were Staphylococcus epidermidis (27.8%), Pseudomonas aeruginosa (18.5%), and Staphylococcus aureus (14.4%). Intravascular cannulae with higher incidence of bacteriemia were the central venous catheters (55%) and the arterial lines (29%). Bacteriemia produced by arterial lines had short free period interval (7.7 days) and in 80% of the cases were produced by Gram negative bacteria whereas that bacteriemia produced by central venous catheters had a long free period (11.2 days) and the most frequent agents were Gram positive bacteria. The overall mortality was 17% and that attributed to the infection 6%. An age above 65 years had a mortality rate of 33% and was identified as the only significant prognostic factor (p less than 0.001). The mean hospitalization period was 49.9 days and the cost of the treatment 830.000 ptas/patient.


Validation of a novel risk score for severity of illness in acute exacerbations of COPD.
Clinicians lack a validated tool for risk stratification in acute exacerbations of COPD (AECOPD). We sought to validate the BAP-65 (elevated BUN, altered mental status, pulse > 109 beats/min, age > 65 years) score for this purpose. We analyzed 34,699 admissions to 177 US hospitals (2007) with either a principal diagnosis of AECOPD or acute respiratory failure with a secondary diagnosis of AECOPD. Hospital mortality and need for mechanical ventilation (MV) served as co-primary end points. Length of stay (LOS) and costs represented secondary end points. We assessed the accuracy of BAP-65 via the area under the receiver operating characteristic curve (AUROC). Nearly 4% of subjects died while hospitalized and approximately 9% required MV. Mortality increased with increasing BAP-65 class, ranging from < 1% in subjects in class I (score of 0) to > 25% in those meeting all BAP-65 criteria (Cochran-Armitage trend test z = -38.48, P < .001). The need for MV also increased with escalating score (2% in the lowest risk cohort vs 55% in the highest risk group, Cochran-Armitage trend test z = -58.89, P < .001). The AUROC for BAP-65 for hospital mortality and/or need for MV measured 0.79 (95% CI, 0.78-0.80). The median LOS was 4 days, and mean hospital costs equaled $5,357. These also varied linearly with increasing BAP-65 score. The BAP-65 system captures severity of illness and represents a simple tool to categorize patients with AECOPD as to their risk for adverse outcomes. BAP-65 also correlates with measures of resource use. BAP-65 may represent a useful adjunct in the initial assessment of AECOPDs.


Effects of long-term high-load exercise on the anatomy of the hip joints: a preliminary report.
The aim of this study was to assess the impact of different sports on hip joint anatomic parameters in athletes. This was a cross-sectional study of eight male trampolinists, eight male weightlifters, and eight male volunteers enrolled in July 2014. Hip joint anatomic parameters were measured from plain radiographs taken at the level of the lesser trochanter center. Data were compared between groups using the χ-test or one-way analysis of variance with the Bonferroni post-hoc test. There were no significant differences among groups in age, height, or weight. Compared with the controls, trampolinists showed higher pelvic width, femoral neck length, metaphyseal width (T0), width 20 mm above T0 (T+20), width 20 mm below T0 (T-20) and center edge (CE) angle, and lower head-trochanter ratio, joint space, neck-shaft angle, and articular cartilage angle (P<0.05). Compared with the controls, weightlifters showed lower pelvic femoral index, joint space, length of femoral neck, eccentricity, neck-shaft, and AC angle, and higher pelvic width, femoral head radius, and CE angle (P<0.05). Compared with trampolinists, weightlifters showed higher head-trochanter ratio and femoral head radius, and lower pelvic femoral index, femoral neck length, eccentricity, T0, T+20, T-20, neck-shaft angle, CE angle, and articular cartilage angle (P<0.05). Long-term high-intensity training causes adaptive changes in the hip joint structure that differ between trampolinists and weightlifters.


Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood.
The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis. The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis. Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b. Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.


[Secondary muscular carnitine deficiency following immunosuppressive treatment].
Carnitine deficiency syndromes can be classified into two groups: primary carnitine deficiency and secondary carnitine deficiency syndromes. A lipid storage myopathy with carnitine deficiency following an immunosuppressive therapy is described in a young man suffering from a possible polymyositis. After treatment with L-carnitine both biochemical and morphological features recovered. A secondary carnitine deficiency syndrome due to an immunosuppressive therapy is supposed.


A prospective study of systolic ejection murmurs and left ventricular outflow tract in boxers.
To investigate the prevalence and progression of murmurs and the development of the left ventricular outflow tract (LVOT) and flow velocities in the great arteries in boxer puppies through adolescence until three years of age. Nineteen boxer puppies with or without a low-intensity murmur, but without evidence of congenital heart disease, were studied prospectively. Examinations were carried out at 7 weeks, 3, 4, 6, 9, 12 and 36 months of age by cardiac auscultation and Doppler echocardiography. Presence and intensity of heart murmurs varied in the same dog and between dogs, but flow velocities did not change. Estimated effective orifice diameter (EOD) and indexed EOD was significantly narrower than measured subvalvular and valvular diameters. The variability in presence and intensity of low-intensity ejection murmurs is high during growth in boxers.


Towards an Action Recognition Framework for Endovascular Surgery.
Objective knowledge about instrument manoeuvres in endovascular surgery is essential for evaluating surgical skills and developing advanced technologies for cathlab routines. To the recent day, endovascular navigation has been exclusively assessed in laboratory scenarios. By contrast, information contained in available fluoroscopy data from clinical cases has been disregarded. In this work, we pioneer a learning-based framework for motion activity recognition in fluoroscopy sequences. The architecture is composed of two networks for instrument segmentation and action recognition. In this preliminary study, we demonstrate feasibility of recognising instrument manoeuvres automatically in our ex vivo datasets.Clinical relevance-The proposed framework contributes to image-based and automated assessment of endovascular tasks. This facilitates robotic control development, surgical education, and smart clinical documentation.


Correlation Analysis of the Tinnitus Handicap Inventory and Distress Network in Chronic Tinnitus: An EEG Study.
Tinnitus is a common disorder with a considerable amount of distress that affects the patient's daily life. No objective tools were approved for measuring tinnitus distress. It can be estimated only by subjective scales and questionnaires, albeit, the Electroencephalography (EEG) studies have reported some alterations regarding tinnitus distress network. This study aimed to investigate the correlation between Tinnitus Handicap Inventory (THI) and the recorded EEG data. A total of 33 chronic tinnitus cases (9 females) with the mean age of 42.67 years were recruited. Their THI scores were collected, and a 3-minute EEG recorded with eye closed at resting-state. The correlation analysis was performed on THI scores and the current density in the selected Region of Interests (ROIs) concerning the distress network for the eight frequency bands. The patients grouped depending on the THI cutoff point of 56 into low and high THI groups, and then the groups were compared for source analysis and functional connectivity between ROIs using standardized low-resolution brain electromagnetic tomography. A significant positive correlation was seen between THI scores and the electrical activity in the Anterior Cingulate Cortex (ACC), the prefrontal cortex, and the parahippocampus for an alpha band (P<0.05) and in the ACC for beta (P<0.01). Source analysis showed significant differences with increased activity in the high THI group for alpha, beta and gamma bands. Functional connectivity was also elevated in the high THI group between the ROIs in alpha and beta bands. THI can be a useful tool for measuring tinnitus distress, and it has a high correlation with EEG data.


Immune evasion strategies of trypanosomes: a review.
Trypanosomes are digenetic protozoans that infect domestic and wild animals, as well as humans. They cause important medical and veterinary diseases, making them a major public health concern. There are many species of trypanosomes that infect virtually all vertebrate taxa. They typically cycle between insect or leech vectors and vertebrate hosts, and they undergo biochemical and morphological changes in the process. Trypanosomes have received much attention in the last 4 decades because of the diseases they cause and their remarkable armamentarium of immune evasion mechanisms. The completed genome sequences of trypanosomes have revealed an extensive array of molecules that contribute to various immune evasion mechanisms. The different species interact uniquely with their vertebrate hosts with a wide range of evasion strategies and some of the most fascinating immune evasion mechanisms, including antigenic variation that was first described in the trypanosomes. This review focuses on the variety of strategies that these parasites have evolved to evade or modulate immunity of endothermic and ectothermic vertebrates.


The cyp2e1-humanized transgenic mouse: role of cyp2e1 in acetaminophen hepatotoxicity.
The cytochrome P450 (P450) CYP2E1 enzyme metabolizes and activates a wide array of toxicological substrates, including alcohols, the widely used analgesic acetaminophen, acetone, benzene, halothane, and carcinogens such as azoxymethane and dimethylhydrazine. Most studies on the biochemical and pharmacological actions of CYP2E1 are derived from studies with rodents, rabbits, and cultured hepatocytes; therefore, extrapolation of the results to humans can be difficult. Creating "humanized" mice by introducing the human CYP2E1 gene into Cyp2e1-null mice can circumvent this disadvantage. A transgenic mouse line expressing the human CYP2E1 gene was established. Western blot and high-performance liquid chromatography/mass spectrometry analyses revealed human CYP2E1 protein expression and enzymatic activity in the liver of CYP2E1-humanized mice. Treatment of mice with the CYP2E1 inducer acetone demonstrated that human CYP2E1 was inducible in this transgenic model. The response to the CYP2E1 substrate acetaminophen was explored in the CYP2E1-humanized mice. Hepatotoxicity, resulting from the CYP2E1-mediated activation of acetaminophen, was demonstrated in the livers of CYP2E1-humanized mice by elevated serum alanine aminotransferase levels, increased hepatocyte necrosis, and decreased P450 levels. These data establish that in this humanized mouse model, human CYP2E1 is functional and can metabolize and activate different CYP2E1 substrates such as chlorzoxazone, p-nitrophenol, acetaminophen, and acetone. CYP2E1-humanized mice will be of great value for delineating the role of human CYP2E1 in ethanol-induced oxidative stress and alcoholic liver damage. They will also function as an important in vivo tool for predicting drug metabolism and disposition and drug-drug interactions of chemicals that are substrates for human CYP2E1.


Time efficient color fringe projection system for 3D shape and color using optimum 3-frequency Selection.
We present a novel color fringe projection system to obtain absolute 3D shape and color of objects simultaneously. Optimum 3-frequency interferometry is used to produce time efficient analysis of the projected fringes by encoding three fringe sets of different pitch into the primary colors of a digital light projector and recording the information on a 3-chip color CCD camera. Phase shifting analysis is used to retrieve subwavelength phase information. Absolute phase across the field is calculated using the 3-frequency method independently at each pixel. Concurrent color data is also captured via the RGB channels of the CCD. Thus full-field absolute shape (XYZ) and color (RGB) can be obtained. In this paper we present the basis of the technique and preliminary results having addressed the issue of crosstalk between the color channels.


The RNAs of the defective interfering Pichinide virus.
A Pichinde persitently infected BHK21/13S culture was established in which defective interfering (DI) virus continued to be synthesized after cessation of plaque-forming virus replication. This DI virus, concentrated from NaCl-polyethylene glycol treated tissue culture fluids, was shown to band over a much broader range than standard virus, in either discontinuous or continuous sucrose gradients. The polyacrylamide gel profile of the RNAs extracted from standard virus contained six components with sedimentation coefficients corresponding to 31, 28, 22, 18, 15 and 4-6S. All RNAs extracted from DI virus preparations, however, did not contain the 22 and 15S species. Furthermore, a new 20S fraction was observed in DI virus taken from cultures which had been maintained for more than 175 generations after the initial infection, whereas it was absent in DI virus synthesized prior to that time.


The special status of actions in causal reasoning in rats.
A. P. Blaisdell, K. Sawa, K. J. Leising, and M. R. Waldmann (2006) reported evidence for causal reasoning in rats. After learning through Pavlovian observation that Event A (a light) was a common cause of Events X (an auditory stimulus) and F (food), rats predicted F in the test phase when they observed Event X as a cue but not when they generated X by a lever press. Whereas associative accounts predict associations between X and F regardless of whether X is observed or generated by an action, causal-model theory predicts that the intervention at test should lead to discounting of A, the regular cause of X. The authors report further tests of causal-model theory. One key prediction is that full discounting should be observed only when the alternative cause is viewed as deterministic and independent of other events, 2 hallmark features of actions but not necessarily of arbitrary events. Consequently, the authors observed discounting with only interventions but not other observable events (Experiments 1 and 2). Moreover, rats were capable of flexibly switching between observational and interventional predictions (Experiment 3). Finally, discounting occurred on the very first test trial (Meta-Analysis). These results confirm causal-model theory but refute associative accounts.


Dietary supplement interactions with antiretrovirals: a systematic review.
Many patients who take antiretroviral drugs also take alternative therapies including dietary supplements. Some drug-supplement combinations may result in clinically meaningful interactions. We aimed to investigate the evidence for dietary supplement interactions with antiretrovirals. A systematic review was conducted using multiple resources including PubMed, Natural Medicine Comprehensive Database, The Review of Natural Products, and Google Scholar. All human studies or case reports evaluating an interaction between a dietary supplement and an antiretroviral were selected for inclusion. Twenty-eight pharmacokinetic studies and case-series/case reports were selected for inclusion. Calcium carbonate, ferrous fumarate, some forms of ginkgo, some forms of garlic, some forms of milk thistle, St. John's wort, vitamin C, zinc sulfate, and multivitamins were all found to significantly decrease the levels of selected antiretrovirals and should be avoided in patients taking these antiretrovirals. Cat's claw and evening primrose oil were found to significantly increase the levels of antiretrovirals and patients should be monitored for adverse effects while taking these dietary supplements with antiretrovirals. This systematic review shows the importance of screening all human immunodeficiency virus patients for dietary supplement use to prevent treatment failure or adverse effects related to an interaction.


The cyclic AMP receptor protein is the main activator of pectinolysis genes in Erwinia chrysanthemi.
The main virulence factors of the phytopathogenic bacterium Erwinia chrysanthemi are pectinases that cleave pectin, a major constituent of the plant cell wall. Although physiological studies suggested that pectinase production in Erwinia species is subjected to catabolite repression, the direct implication of the cyclic AMP receptor protein (CRP) in this regulation has never been demonstrated. To investigate the role of CRP in pectin catabolism, we cloned the E. chrysanthemi crp gene by complementation of an Escherichia coli crp mutation and then constructed E. chrysanthemi crp mutants by reverse genetics. The carbohydrate fermentation phenotype of the E. chrysanthemi crp mutants is similar to that of an E. coli crp mutant. Furthermore, these mutants are unable to grow on pectin or polygalacturonate as the sole carbon source. Analysis of the nucleotide sequence of the E. chrysanthemi crp gene revealed the presence of a 630-bp open reading frame (ORF) that codes for a protein highly similar to the CRP of E. coli. Using a crp::uidA transcriptional fusion, we demonstrated that the E. chrysanthemi CRP represses its own expression, probably via a mechanism similar to that described for the E. coli crp gene. Moreover, in the E. chrysanthemi crp mutants, expression of pectinase genes (pemA, pelB, pelC, pelD, and pelE) and of genes of the intracellular part of the pectin degradation pathway (ogl, kduI, and kdgT), which are important for inducer formation and transport, is dramatically reduced in induced conditions. In contrast, expression of pelA, which encodes a pectate lyase important for E. chrysanthemi pathogenicity, seems to be negatively regulated by CRP. The E. chrysanthemi crp mutants have greatly decreased maceration capacity in potato tubers, chicory leaves, and celery petioles as well as highly diminished virulence on saintpaulia plants. These findings demonstrate that CRP plays a crucial role in expression of the pectinolysis genes and in the pathogenicity of E. chrysanthemi.


"I Want to Be Really Clear": What Male Sex Workers Want to Clarify With Prospective Clients Before Agreeing to Meet for Sex.
Men who have sex with men (MSM) and engage in sex work (MSW) frequently meet clients through dating/hookup apps. This provides an opportunity to discuss the parameters of the exchange prior to meeting and to learn things about the prospective client and the risks he might pose. Limited research has examined the specific issues or topics MSWs discuss with clients before agreeing to meet. We analyzed interview data from a sample of 180 MSWs from eight U.S. cities who engaged in exchange sex with clients they had primarily met through dating/hookup apps and websites. Participants typically asked about clients' sexual interests and expectations regarding what will transpire when they meet to make sure they were compatible with their own boundaries and limitations. Most participants inquired about clients' sexual health and often discussed condom use. Assertiveness and communication skills training might help MSWs negotiate encounters with clients that promote health and safety.


A novel high-order associative memory system via discrete Taylor series.
This paper proposes a novel high-order associative memory system (AMS) based on the discrete Taylor series (DTS). The mathematical foundation for the new AMS scheme is derived, three training algorithms are proposed, and the convergence of learning is proved. The DTS-AMS thus developed is capable of implementing error-free approximation to multivariable polynomial functions of arbitrary order. Compared with cerebellar model articulation controllers and radial basis function neural networks, it provides higher learning precision and less memory request. Furthermore, it offers less training computation and faster convergence rate than that attainable by multilayer perceptron. Numerical simulations show that the proposed DTS-AMS is effective in higher order function approximation and has potential in practical applications.


Third ventricular cavernous angioma.
Third ventricular cavernous angiomas are rare vascular malformations of the brain. We report an eight-year old boy with a rare third ventricular cavernous angioma that hemorrhaged presenting with symptoms of acute hydrocephalus. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) showed a heterogenous ill-defined, solid and cystic intraventricular mass in the third ventricle which was mildly enhanced with contrast and there was associated hydrocephalus. The mass was removed with success and follow up after two years revealed no neurological abnormalities.


Herpes Simplex Virus Type 2 Myelitis: Case Report and Review of the Literature.
Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.


Experimental and molecular dynamics characterization of dense microemulsion systems: morphology, conductivity and SAXS.
Microemulsions are exciting systems that are promising as tuneable self-assembling templating reaction vessels at the nanoscale. Determination of the nano-structure of microemulsions is, however, not trivial, and there are fundamental questions regarding their design. We were able to reproduce experimental data for an important microemulsion system, sodium-AOT-n-heptane-water, using coarse-grained simulations involving relatively limited computational costs. The simulation allows visualization and deeper investigation of controversial phenomena such as bicontinuity and ion mobility. Simulations were performed using the Martini coarse-grained force field. AOT bonded parameters were fine-tuned by matching the geometry obtained from atomistic simulations. We investigated several compositions with a constant ratio of surfactant to oil while the water content was varied from 10 to 60% in weight. From mean square displacement calculation of all species, it was possible to quantify caging effects and ion mobility. Average diffusion coefficients were calculated for all charged species and trends in the diffusion coefficients were used to rationalize experimental conductivity data. Especially, the diffusion coefficient of charged species qualitatively matched the variation in conductivity as a function of water content. The scattering function was calculated for the hydrophilic species and up to 40% water content quantitatively matched the experimental data obtained from small angle X-ray scattering measurements. For higher water contents, discrepancies were observed and attributed to a nearby phase separation. In particular, bicontinuity of water and oil was computationally visualized by plotting the coordinates of hydrophilic beads. Equilibrated coarse-grained simulations were reversed to atomistic models in order both to compare ion mobility and to catch finer simulation details. Especially, it was possible to capture the intimate ion pair interaction between the sodium ion and the surfactant head group.


Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents.
Toxoplasma gondii is an opportunistic pathogen responsible for toxoplasmosis. T. gondii is a purine auxotroph incapable of de novo purine biosynthesis and depends on salvage pathways for its purine requirements. Adenosine kinase (EC.18.104.22.168) is the major enzyme in the salvage of purines in these parasites. 6-Benzylthioinosine and analogues were established as "subversive substrates" for the T. gondii, but not for the human adenosine kinase. Therefore, these compounds act as selective anti-toxoplasma agents. In the present study, a series of N(6)-benzyladenosine analogues were synthesized from 6-chloropurine riboside with substituted benzylamines via solution phase parallel synthesis. These N(6)-benzyladenosine analogues were evaluated for their binding affinity to purified T. gondii adenosine kinase. Furthermore, the anti-toxoplasma efficacy and host toxicity of these compounds were tested in cell culture. Certain substituents on the aromatic ring improved binding affinity to T. gondii adenosine kinase when compared to the unsubstituted N(6)-benzyladenosine. Similarly, varying the type and position of the substituents on the aromatic ring led to different degrees of potency and selectivity as anti-toxoplasma agents. Among the synthesized analogues, N(6)-(2,4-dimethoxybenzyl)adenosine exhibited the most favorable anti-toxoplasma activity without host toxicity. The binding mode of the synthesized N(6)-benzyladenosine analogues were characterized to illustrate the role of additional hydrophobic effect and van der Waals interaction within an active site of T. gondii adenosine kinase by induced fit molecular modeling.


Cross vascular risk for first and recurrent hospitalised atherothrombosis determined retrospectively from linked data.
To determine the sex-specific and age-specific risk ratios for the first-ever and recurrent hospitalisation for cerebrovascular, coronary and peripheral arterial disease in persons with other vascular history versus without other vascular history in Western Australia from 2005to 2007. Cross-sectional linkage study. Hospitalised population in a representative Australian State. All persons aged 34-85 years between 1 January 2005 and 31 December 2007 were hospitalised with a principal diagnosis of atherothrombosis. Person-linked file of statutory-collected administrative morbidity and mortality records. Sex-specific and age-specific risk ratios for the first-ever and recurrent hospitalisations for symptomatic atherothrombosis of the brain, coronary and periphery using a 15-year look-back period lead to the determining of prior events. Over 3 years, 40 877 (66% men; 55% first-ever) were hospitalised for atherothrombosis. For each arterial territory, age-specific recurrent rates were higher than the corresponding first-ever rates, with the biggest difference seen in the youngest age groups. For all types of first-ever atherothrombosis, the rates were higher in those with other vascular history and the risk ratios declined with an advancing age (trend: all p<0.0001) and remained significantly >1 even for 75-84 years old. However, for recurrent events, the rates were marginally higher in those with other vascular history and no risk ratio age trend was apparent with several not significantly >1 (trend: all p>0.13). This study of hospitalised atherothrombosis suggests first-events predominate and that the risk of further events in the same or other arterial territory is very high for all ages and both sexes, accentuating the necessity for an early and sustained active prevention.


T-cell co-signalling molecules in graft-versus-host disease.
Allogeneic stem cell transplantation (allo SCT) is now frequently performed for the treatment of haematological malignancies and aplastic anaemia. However, graft-versus-host disease (GVHD) is still the major complication after allo SCT, producing immune deficiency, infection, organ damage and, occasionally, patient death. The antigen-specific signal mediated by the T-cell receptor (TCR) is essential for activation of T-cells; however, additional co-stimulatory signals are required for complete T-cell activation. Therefore, blocking strategies of co-stimulatory signals have been evaluated as targets of therapeutic intervention for GVHD after allo SCT. In a mouse bone-marrow transplantation (BMT) model, the administration of CTLA4-Ig, which blocks the interaction of CD28 on T-cells and B7 molecules on antigen-presenting cells (APCs), can prolong survival of allo BMT recipients, although this effect was not complete. In addition, the anti-CD40L (CD154) monoclonal antibody (mAb), which can interfere with the interaction of CD154 on T-cells and CD40 on APCs, can induce long-term graft survival in the murine model. Combined administration of CTLA4-Ig and anti-CD40L mAb can prevent allograft rejection in primates. Therefore, it seems the most powerful method to prevent the alloimmune response in vivo. The Fas/Fas ligand pathway is also involved in pathogenesis of GVHD. Anti-FasL mAb can reduce the mortality of GVHD and improve intestinal lesions. Recently, it was reported that donor bone marrow treated ex vivo using CTLA4-Ig reconstituted haematopoiesis in vivo with a relatively low risk of GVHD in human allo BMT. Therefore, selective blocking strategies for T-cell co-signalling might be useful for the prevention of GVHD in human allo SCT.


Recent advances in nanoparticle carriers for photodynamic therapy.
This review summarizes recent advances in the development of nanoparticles (NPs) for efficient photodynamic therapy (PDT), particularly the development and application of various NPs based on organic and inorganic materials. PubMed database was used for literature search with the terms including NP, nanomedicine, PDT, photosensitizer (PSs), and drug delivery. For successful PDT, it is essential to deliver PSs to target disease sites. A number of NPs have been developed and tested as the carriers for both imaging and therapy, an approach termed "nanomedicine". Many studies of NP carriers showed increased water solubility and stability of PSs for in vivo injection, and these NP carriers provided benefits including longer circulation in blood and higher accumulation of PSs at disease sites. This review describes new techniques in PDT such as aggregation-induced emission (AIE) and luminescence-based PDT, and provides insights on NPs and PDT for biomedical researchers working to develop or apply NPs in efficient PDT.


Verification of medical guidelines in KIV.
We propose to use computerised medical guidelines as models for verification tools, so they can be validated with medical properties. To test the applicability we provide an implementation of the semantics of the medical planning language Asbru and also provide a formalised guideline for the treatment of breast cancer. With this case study we conduct experiments testing different proof techniques to cope with several challenges which guidelines provide.


Spontaneous current pulses through developing fucoid eggs.
Using a newly developed, extracellular vibrating electrode, we can now measure the electrical currents that traverse a single developing cell. We have studied the eggs of the common seaweed, Pelvetia, during their first 2 days of development and find that the endogenous electrical current through them includes a pulse component as well as a relatively steady component. Both of these enter the egg's growing tip and leave the rest of the embryo. The current pulses first appear a few hours after growth begins and have a characteristic shape that is independent of amplitude. They have a duration of about 100 sec, an average frequency of 1-5 per hr, and enter with peak surface intensities of 3-10 (and rarely up to 30) muA/cm(2). By the two-cell stage they account for about a fourth of the total transembryonic current. Since they may overlap to any degree and (as is documented elsewhere) are generally accompanied by peak membrane depolarizations of only 2-6 mV, their course does not seem to be voltage-controlled. Thus, they seem essentially different from action potentials. We also find that the rate at which the egg grows in length is roughly proportional to the size of the steady current traversing it.


Effect on neuromuscular transmission of repeated administration of an organophosphorus compound, metrifonate, during treatment of children with urinary schistosomiasis.
Muscle action potential amplitude recorded from abductor pollicis brevis in response to nerve stimulation was measured in 55 children during treatment of urinary schistosomiasis with metrifonate (3 doses at 2 weekly intervals). Mean erythrocyte cholinesterase activity was 52-75% of pretreatment value in different groups when examined electrophysiologically. Twenty-six children acted as controls. There was no difference in amplitude between control and exposed subjects 2 weeks after the 2nd dose. Six hours after the 3rd dose, amplitude was larger in some subjects. This effect was not related to dose or degree of cholinesterase inhibition and was thought unlikely to be the result of treatment. Three children who received the highest dose of metrifonate had developed repetitive activity 6 hr later. The criteria for its identification are described.


Identification of visual paternity cues in humans.
Understanding how individuals identify their relatives has implications for the evolution of social behaviour. Kinship cues might be based on familiarity, but in the face of paternity uncertainty and costly paternal investment, other mechanisms such as phenotypic matching may have evolved. In humans, paternal recognition of offspring and subsequent discriminative paternal investment have been linked to father-offspring facial phenotypic similarities. However, the extent to which paternity detection is impaired by environmentally induced facial information is unclear. We used 27 portraits of fathers and their adult sons to quantify the level of paternity detection according to experimental treatments that manipulate the location, type and quantity of visible facial information. We found that (i) the lower part of the face, that changes most with development, does not contain paternity cues, (ii) paternity can be detected even if relational information within the face is disrupted and (iii) the signal depends on the presence of specific information rather than their number. Taken together, the results support the view that environmental effects have little influence on the detection of paternity using facial similarities. This suggests that the cognitive dispositions enabling the facial detection of kinship relationships ignore genetic irrelevant facial information.


Acute Kidney Injury Impairs Postnatal Renal Adaptation and Increases Morbidity and Mortality in Very Low-Birth-Weight Infants.
This study aims to estimate the impact of acute kidney injury (AKI) on postnatal renal adaptation, morbidity, and mortality in very low-birth-weight (VLBW) infants. We conducted a retrospective study of 457 VLBW infants admitted to a tertiary level neonatal intensive care unit (NICU) between July 2009 and April 2015. We compared patient characteristics, risk factors, serum creatinine trends, and adverse outcomes in infants with and without AKI using multivariate logistic regression analysis. Incidence of AKI was 19.5%. On multivariate analysis, postnatal risk factors such as patent ductus arteriosus and vancomycin use were significantly associated with AKI. Infants with AKI had significantly higher mortality; 25/89 (28%) versus 15/368 (4%) (p < 0.001). Among survivors with AKI, bronchopulmonary dysplasia (BPD) was more prevalent (52.8 vs. 23.9%, p < 0.001), serum creatinine remained elevated for a longer duration and median length of stay extended by 38 days. Presence of AKI was associated with impaired postnatal renal adaptation, BPD, significantly longer stay in the NICU and higher mortality.


Total synthesis of the fumiquinazoline alkaloids: solution-phase studies.
Biomimetic total syntheses of glyantrypine, fumiquinazoline F, fumiquinazoline G, and fiscalin B were achieved in four steps from tryptophan methyl ester. In the key step, the anthranilamide residue in a linear tripeptide is dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The benzoxazines subsequently undergo rearrangement to the natural products via an amidine intermediate. This dehydrative oxazine to quinazoline route is applicable to a broad range of N-acylanthranilamides, including sterically hindered cases.


Healthcare-associated pneumonia: approach to management.
Healthcare-associated pneumonia patients have worse outcomes and a different microbiologic profile than those with community-acquired pneumonia, including a greater risk for multidrug-resistant (MDR) organism infection. Risks include hospitalization for 2 or more days within 90 days, presentation from a nursing home or long-term care facility, attending a hospital or hemodialysis clinic, receiving intravenous therapy within 30 days, and immunosuppression. Ability to predict infection with MDR organisms varies, and the relative frequency of MDR organisms varies by geographic region. Initial treatment is broad-spectrum empiric antibiotics.


Comprehensive characterization of the human pancreatic proteome for bioengineering applications.
Interactions between the pancreatic extracellular matrix (ECM) and islet cells are known to regulate multiple aspects of islet physiology, including survival, proliferation, and glucose-stimulated insulin secretion. Recognizing the essential role of ECM in islet survival and function, various engineering approaches have been developed that aim to utilize ECM-based materials to recreate a native-like microenvironment. However, a major impediment to the success of these approaches has been the lack of a robust and comprehensive characterization of the human pancreatic proteome. Herein, by combining mass spectrometry (MS) and multiplex ELISA, we have provided an improved workflow for the in-depth profiling of the proteome, including minor constituents that are generally underrepresented. Moreover, we have further validated the effectiveness of our detergent-free decellularization protocol in the removal of cellular proteins and retention of the matrisome. It has also been established that the decellularized ECM and its derivatives can provide more tissue-specific cues than traditionally used biological scaffolds and are therefore more physiologically relevant for the development of hydrogels, bioinks and medium additives, in order to create a pancreatic niche. The data generated in this study would contribute significantly to the efforts of comprehensively defining the ECM atlas and also serve as a standard for the human pancreatic proteome to provide further guidance for design and engineering strategies for improved tissue engineering scaffolds.


Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas.
An excess risk of second malignancies has been reported in survivors of Ewing's sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewing's sarcoma and to identify possible causal factors. Information was derived from a data base that included 266 survivors of Ewing's sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated. After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P = .002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy. The overall risk of second malignancies after Ewing's sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.


Forecasting patient outcomes in the management of hyperlipidemia.
To forecast adult patient outcomes in the management of hyperlipidemia using adult National Health and Examination Survey III (NHANES III) population statistics and National Cholesterol Education Program (NCEP) guidelines for goals of therapy. Review of the hyperlipidemia drug therapy English-language medical literature with emphasis on randomized controlled trials of more than 6 weeks' duration published in the last 7 years, product package inserts, US Food and Drug Administration submission information, and NHANES III population statistics. Data were extracted from studies of lipid-lowering therapy to modify low-density lipoprotein (LDL) levels for primary and secondary prevention of coronary heart disease. The data that were evaluated included sample size, study design, therapeutic intervention, length of study, percentage change in LDL levels, and patient demographics. Cumulative frequency curves of the LDL distribution among the US adult population were constructed. The mean efficacy of drug therapy from qualified studies was used to extrapolate the percentage of the population expected to respond to the intervention and to forecast the patient outcome. A useful tool for clinicians was constructed to approximate the percentage of patients, based on risk stratification, who would reach NCEP target goal after a given pharmacotherapeutic intervention to decrease LDL levels.


Grapevine fleck virus-like viruses in Vitis.
Two sets of degenerate primers for the specific amplification of 572-575 nt and 386 nt segments of the methyltransferase and RNA- dependent RNA polymerase cistrons of members of the genera Tymovirus and Marafivirus and of the unassigned virus Grapevine fleck virus (GFkV) were designed on the basis of available sequences. These primers were used for amplifying and subsequent cloning and sequencing part of the open reading frame 1 of the genome of GFkV, Grapevine asteroid mosaic-associated virus (GAMaV) and of another previously unreported virus, for which the name Grapevine red globe virus (GRGV) is proposed. Computer-assisted analysis of the amplified genome portions showed that the three grapevine viruses are phylogenetically related with one another and with sequenced tymoviruses and marafiviruses. The relationships with tymoviruses was confirmed by the type of ultrastructural modifications induced in the host cells. RdRp-specific degenerate primers were successfully used for the aspecific detection of the three viruses in crude grapevine sap extracts. Specific virus identification was obtained with RT-PCR using antisense virus-specific primers.


Prenylation of proteins by the intact lens.
To describe and identify proteins prenylated by the intact rat lens. Lenses from young rats were incubated for 24 hours in TC199 medium containing 22 microM lovastatin and 110 microCi/ml [3H]mevalonolactone. Proteins of the epithelium and fiber cells were separated by high-performance liquid chromatography (HPLC) and one- and two-dimensional electrophoresis, and the 3H label was detected by fluorography. Treatment of labeled proteins with methyl iodide released isoprenes that were identified by HPLC analysis. The identity of the prenylated proteins was probed by N-terminal sequence analysis and matrix-assisted, laser desorption ionization-mass spectrometry (MALDI-MS). The pattern of protein prenylation by epithelial and fiber cells was similar. Most of the labeled proteins were water insoluble and were assumed to be membrane associated. A group of 21-kDa to 29-kDa proteins were most intensely labeled and were modified mainly with geranylgeranyl. A highly labeled, approximately 80-kDa insoluble protein and a lesser labeled, 64-kDa soluble protein were the only other significant prenylated proteins. Both were farnesylated. MALDI-MS analysis suggested that the 80-kDa protein is a cytokeratin. N-terminal sequence analysis indicated that the 64-kDa soluble protein is beta-tubulin. A limited set of proteins are prenylated by the young rat lens. The 21-kDa to 29-kDa proteins were modified mainly by geranylgeranyl and are likely members of the numerous small GTP binding proteins. The authors express caution about accepting the identities of the 64-kDa and 80-kDa proteins as beta-tubulin and cytokeratin-1, respectively--proteins in these families do not contain the required CAAX motif. The 80-kDa farnesylated protein could be novel and unique to the lens, because no farnesylated protein of this size has been previously reported.


The Impact of COVID-19 on Treatment Practices for Patients With Early Breast Cancer: A Cross-Sectional Study From a Large Cancer Center in Italy.
The Coronavirus Disease 2019 (COVID-19) has disrupted health services worldwide. The evidence on the impact of the pandemic on cancer care provision, however, is conflicting. We aimed to audit the management of patients diagnosed with early breast cancer (EBC) during the pandemic in a large, tertiary-level cancer center in Italy. We conducted a cross-sectional study to track the route to first treatment for patients diagnosed with EBC during 2019, 2020, and 2021. We abstracted data for all consecutive patients referred to the Veneto Institute of Oncology (Padua, Italy). We defined as point of contact (POC) the date of the first consultation with a breast cancer specialist of the breast unit. First treatment was defined as either upfront surgery or neoadjuvant chemotherapy (NACT). We reviewed medical records for 878 patients for whom an MDT report during 2019-2021 (April through June) was available. Of these, 431 (49%) were eligible. The proportion of screen-detected tumors was larger in 2019 and 2021 than in 2020 (59%). Conversely, the proportion of screen-detected tumors was offset by the proportion of palpable tumors in 2020 (P = .004). Distribution of tumor and nodal stage was unchanged over time, but in situ tumors were slightly fewer in 2020 than in 2019 or 2021. The adjusted odds ratio for treatment delay (45 days or more) was 0.87 for 2020 versus 2019 (95% CI, 0.5-1.53) and 0.9 for 2021 versus 2019 (95% CI, 0.52-1.55). There was no evidence for major changes in the management of patients with EBC during 2019-2021 and no treatment delays were observed. Our findings suggest that more women presented with palpable nodules at diagnosis, but the stage distribution did not change over time. Validation on a larger cohort of patients is warranted to robustly assess the impact of the COVID-19 pandemic on treatment practices for patients with EBC.


Optimal conditions for the study of surface topography of granulosa cell cultures.
The purpose of this study was to define optimal substrate conditions for permitting correlation of cell surface morphology with progesterone secretion by luteinized granulosa cells in vitro. Some 3-5 x 10(5) granulosa cells were obtained from preovulatory follicles of PMS-LH treated rats and plated upon carbon, poly-L-lysine or collagen-coated glass coverslips within plastic multiwells or upon Cytodex, Biosilon or poly-L-lysine coated Sephadex beads within siliconized glass roller tubes. Cells were maintained at 36.5 degrees C in 1.0 ml medium with and without 1.0 microgram purified prolactin (r, bPRL). Spent medium was assayed for progesterone by RIA. Cultures were processed for SEM observation of cell surface features. Results indicate that: 1) cells cultured in multiwells upon carbon, poly-L-lysine or glass grow as flattened monolayers but demonstrate considerable tearing distortion following routine processing for SEM, 2) cells cultured upon collagen-coated coverslips or microcarriers within roller tubes maintain a more spherical shape, exhibit the least distortion of surface fine structure and secrete increased amounts of progesterone in the presence of PRL. It is concluded that the use of Cytodex microcarriers for culturing granulosa cells permits optimal conditions for both progesterone secretion and maintenance of surface morphology.


Human papillomavirus DNA replication mediated by simian virus 40 T antigen in trans.
The putative E1 gene product of papillomaviruses is thought to be involved in the initiation of viral replication, as large-T antigen (T antigen) is in the case of polyomaviruses. Mouse cell lines cloned after transformation by a plasmid consisting of the simian virus 40 (SV40) early region and the complete genome of human papillomavirus type 16 (HPV16) maintained episomal plasmid DNA. In contrast, the DNAs of either SV40 or HPV16, when employed separately in transfection experiments, were consistently integrated into the host DNA. To test the hypothesis that SV40 T antigen might be involved in the replication of the hybrid plasmids, HPV16 DNA was used in a transient replication assay for transfection of either CV-1 or COS-7 cells. The HPV16 DNA replicated to a high copy number in the T antigen-producing COS-7 cells, but failed to replicate in the CV-1 cells. To define the HPV16 sequences that were essential for the plasmid maintenance in SV40 T antigen-producing cells, restriction fragments of HPV16 were analysed for their replication capacity in COS-7 cells. Here it is reported that the presence of the coding region of the putative E1 gene product of HPV16 together with the 5' transcriptional control elements is essential and is sufficient to support plasmid replication mediated by SV40 T antigen in trans.


Post COVID-19 ENERGY sustainability and carbon emissions neutrality.
This review covers the recent advancements in selected emerging energy sectors, emphasising carbon emission neutrality and energy sustainability in the post-COVID-19 era. It benefited from the latest development reported in the Virtual Special Issue of ENERGY dedicated to the 6th International Conference on Low Carbon Asia and Beyond (ICLCA'20) and the 4th Sustainable Process Integration Laboratory Scientific Conference (SPIL'20). As nations bind together to tackle global climate change, one of the urgent needs is the energy sector's transition from fossil-fuel reliant to a more sustainable carbon-free solution. Recent progress shows that advancement in energy efficiency modelling of components and energy systems has greatly facilitated the development of more complex and efficient energy systems. The scope of energy system modelling can be based on temporal, spatial and technical resolutions. The emergence of novel materials such as MXene, metal-organic framework and flexible phase change materials have shown promising energy conversion efficiency. The integration of the internet of things (IoT) with an energy storage system and renewable energy supplies has led to the development of a smart energy system that effectively connects the power producer and end-users, thereby allowing more efficient management of energy flow and consumption. The future smart energy system has been redefined to include all energy sectors via a cross-sectoral integration approach, paving the way for the greater utilization of renewable energy. This review highlights that energy system efficiency and sustainability can be improved via innovations in smart energy systems, novel energy materials and low carbon technologies. Their impacts on the environment, resource availability and social well-being need to be holistically considered and supported by diverse solutions, in alignment with the sustainable development goal of Affordable and Clean Energy (SDG 7) and other related SDGs (1, 8, 9, 11,13,15 and 17), as put forth by the United Nations.